Highest impact structures

Two Types of "Impact"
Macromolecular 3D structures can impact scientific understanding and/or save lives by contributing to Structure-based drug design. The first list below, Highest Impact Macromolecular Structures of All Time, concerns impact on scientific understanding. A separate list below concerns Structures Saving The Most Lives.

Highest Impact Macromolecular Structures of All Time
Below you are invited to list pages about structures that you believe to be among the highest impact since the first empirical macromolecular structures were determined. Please do not list a structure unless you provide a justification in the form of a brief description of its impact.

More about some of the earliest structures and their PDB files is here.

This list is in chronological order.


 * 1953 - DNA double helix (B form): Although Watson and Crick's model was theoretical, it was essentially correct, and for the first time explained the ability of genes to be faithfully copied during cell division. It was not confirmed by atomic resolution X-ray crystallography until 1973, using RNA dinucleotide crystals. A full turn of B form DNA was not solved until 1980 (cf. 1bna), 27 years after Watson and Crick's model. More: click on DNA at the Atlas of Macromolecules


 * 1958 - Myoglobin: As the first protein structure that was determined, it is hard to exaggerate its impact. Before this structure, proteins were widely believed to be colloidal, and protein crystals were expected to contain highly symmetrical structures. The irregular fold of myoglobin (see photo of an early low-resolution model at Nobel Prizes for 3D Molecular Structure) was a huge surprise.


 * 1965 - Lysozyme: The first enzyme crystal structure determination and the third protein structure overall. The structure provided the first view of a beta-sheet, and the first view of the three-dimensional arrangement of catalytic amino acid residues in an active site. An inhibitor-bound structure determined in the same year showed the non-covalent interactions between binding cleft and the ligand. Lysozyme is a model enzyme for studying crystallization, the impact of crystal packing on structure, catalytic activity in the crystalline state, and the consequences of mutations on structure and activity.


 * 1970 - Deoxy-hemoglobin: M. Perutz' second hemoglobin structure proved to be at least as important as the first, published two years earlier, as it demonstrated that a protein can have several conformations, and that its physiological role depends on how it changes from one to the other.


 * 1974 - Transfer RNA: The first 3D RNA structure solved; tRNA remained the only biological RNA solved crystallographically for around two decades. This landmark structure served as a foundation for our understanding of RNA structure and translation in general.


 * 1978 - Tobacco bushy stunt virus: S. Harrison offered the first atomic scale image of a complete biological object, a plant virus. It was a technical feat, and revealed rules of architecture that, a few years later (1985), were shown to apply to human pathogens such as the common cold and the poliomyelitis viruses.


 * 1987 - Major histocompatibility complex class I: Created a paradigm shift in cellular immunology by explaining how MHC is involved in presenting hidden intracellular proteins to T lymphocytes. During the decade prior to this structure, this was a constantly debated but very murky mystery.


 * 2000 - Ribosome: This structure surprised almost everyone by showing that peptidyl transferase is a ribozyme, rather than a protein enzyme. It won the 2009 Nobel Prize in Chemistry.

Structures Saving The Most Lives
Structures of the following molecules were used in structure-based drug design, and the resulting drugs have saved large numbers of lives.


 * Influenza virus neuraminidase structure was used in designing the neuraminidase inhibitors oseltamivir (Tamiflu&reg;) and zanamivir (Relenza&reg;). Roche, the manufacturer of Tamiflu, estimates that 50 million people have been treated with this drug . The Cochrane Collaboration concluded that neuriminidase inhibitors "are effective in preventing and treating the symptoms and complications of influenza" . Influenza kills hundreds of thousands of people annually, including 40,000 in the United States . While it is difficult to estimate accurately the number of lives saved by these drugs, the number seems likely to be very large.


 * HIV protease structure was used in designing anti-retroviral protease inhibitors that, as a component of Highly Active Anti-Retroviral Therapy (HAART), have added many high-quality years to the lives of HIV infected individuals. While HAART greatly extends life in HIV infected patients, it is not a cure, and these patients may eventually succumb to AIDS. For more, please see AIDS Before Protease Inhibitors & HIV Protease Inhibitors: A Breakthrough.